Anti-metabolic, cytotoxic therapies for cancer have achieved success in extending the lives of people afflicted with this disease. The goal of this approach to cancer treatment, at its limit, is the complete eradication of cancer cells. Elimination of all residual cancer cells results in cure, although emergence of drug resistance or of more aggressive disease often hampers this outcome. The goal of cytostatic cancer therapies is to retard cellular proliferation rather than eliminate all cancer cells. Controlling the growth of cancer would, at one extreme, effectively render the disease impotent. Failure to completely control the growth of cancer would nonetheless be clinically valuable if, for example, cytostatic therapy significantly extended the duration of remissions induced by cytotoxic agents.
Malignant transformation is often associated with the acquisition of a phenotype that is consistent with an abnormally high sensitivity to ambient concentrations of growth factors. In prostate cancer, for example, the source of such growth factors can be autocrine, from the cancer cells themselves, or from the surrounding stroma in a paracrine fashion (Russel et al. (1998) Clin. Chem. 44(4): 705-723, Steiner, M. S. (1993) Urology 42: 99-110). The molecular role of growth factors and their corresponding receptors in malignant transformation and cancer progression is complex and not yet well understood.
Growth factor receptors are often linked to the pathway that regulates calcium homeostasis. The mitogenic interaction of a growth factor with its receptor can activate a pathway that includes enhancement of the entry of extracellular Ca2+. Engagement of a growth factor receptor by an appropriate ligand results in the activation of phospholipase C by tyrosine phosphorylation (Exton, J. H. Ann. Rev. Pharmacol. Toxicol, 36: 481-509). Activated phospholipase C metabolizes phosphatidyl inositol bisphosphate to produce diacylglycerol and inositol 1,4,5-triphosphate (Berridge et al. (1984) Nature 312: 315-321). Inositol triphosphate releases Ca2+ from an internal storage depot, and this release of intracellular Ca2+ triggers the influx of extracellular Ca2+ (Berridge, supra).
The role of enhanced Ca2+ entry in the proliferation of cancer cells is not well understood. It has been shown, however, that proliferation of at least some cancer cell lines can be slowed or stopped at specific points in the cell cycle by removal of extracellular Ca2+. (Meldolesi, J. (1995) Nat. Med. 1: 512-513; Alessandro et al. (1996) In Vivo 10:153-160). Consistent with this observation is that a drug that blocks Ca2+ entry can retard the metastasis of human melanoma cells in immune deficient mice (Benzaquen et al. (1995) Nat. Med. 1: 534-540).
While the role of Ca2+ entry in cancer cell proliferation has been known for some time, the use of directed Ca2+ entry antagonists for the suppression of Ca2+ influx and treatment of cancer had not been developed until now. For the first time and in accordance with the present invention, compounds have been developed that block growth factor receptor-linked Ca2+ entry and growth factor-driven cellular proliferation both in vitro and in vivo. The compounds of the present invention are useful for inhibiting Ca2+ entry into and proliferation of cancer cells, such as breast and prostate cancer cells, without apparent toxicity.